Objective: To assess the severity of the acute toxicity and sub-acute toxicity of a novel recombinant human granulocyte-colony stimulating factor a (rhG-CSFa) in mice and the dose-effect relationship. Methods: Total 80 mice (equal numbers of male and female) were randomized into eight groups for the acute toxicity study: six groups were subcutaneously or intravenously injected with rhG-CSFa at 34, 345, and 3450 μg/kg, respectively, and two groups were injected with normal saline as the control. The physical status and body weight were monitored for the next 10 days. Another 50 mice (equal numbers of male and female) were randomized into five groups for the sub-acute toxicity study: four groups were subcutaneously injected with rhG-CSFa at 1.1, 11.5, 115, and 1150 μg/kg, respectively, and the other group was treated with normal saline as the control. The mice received injections for 3 weeks. The physical status and body weight were monitored. The mice were sacrificed after the last rhG-CSFa administration. The numeration of leukocyte, bone marrow smear and blood smear were performed for each mouse. Results: Acute toxicity study indicated that no significant acute toxicity was observed in mice received rhG-CSFa administration. There was no significant difference of weight between the control and the treatment groups (P>0.05). Further study of sub-acute toxicity revealed that the absolute number of granular leukocytes in mice from three treatment groups were higher compared with the control group (P<0.01), and the increase of granular leukocytes was rhG-CSFa dose-dependent. No significant abnormalities were observed in this study. Conclusions: No significant toxicity was observed in mice received rhG-CSFa administration in the acute and sub-acute toxicity studies.
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Objective: To study the pharmacokinetics of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and to determine the proteolytic rates of rhG-CSFa in the whole blood and serum of rats in vitro. Methods: The pharmacokinetics of rhG-CSFa and conventional (wild type, WT) granulocyte colony-stimulating factor (G-CSF) were investigated in Sprague-Dawley rats which received either intravenous or subcutaneous injection of rhG-CSFa or WT G-CSF at three different doses (20, 50, or 100 μg/kg). The blood samples of rats were collected at multiple time points (from 0.08 to 12 h) and the concentrations of rhG-CSFa and WT G-CSF in serum were determined with a sandwich enzyme-linked immunosorbent assay (ELISA). For the study of proteolytic rates in vitro, the concentrations of rhG-CSFa or WT G-CSF were determined at 3-minute intervals after addition of the respective drug to rat's whole blood or serum. Results: Pharmacokinetic analysis of serum rhG-CSFa or WT G-CSF levels indicated that, at each dose tested, for either route of drug administration, the area under concentration-time curve values and the maximum serum concentration of rhG-CSFa were higher than those of WT G-CSF, and the serum half life of rhG-CSFa was longer than that of WT G-CSF. Subsequent in vitro whole blood and serum stability study showed that the rates of drug degradation in WT G-CSF were 1.8 folds and 1.5 folds higher than those in rhG-CSFa, respectively. Conclusion: rhG-CSFa has better serum and whole blood stability in vitro and higher bioavailability in vivo as compared to WT G-CSF.
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